Selection of novel analogs of thalidomide with enhanced tumor necrosis factor alpha inhibitory activity
Selection of novel analogs of thalidomide with enhanced tumor necrosis factor alpha inhibitory activity
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DOI：
10.1007/bf03401909
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发表时间：
1996-07-01
影响因子：
5.7
通讯作者：
Kaplan, G
中科院分区：
文献类型：
--
作者：
Corral, LG;Muller, GW;Kaplan, G
背景：肿瘤坏死因子（TNF α）被认为介导炎症反应的保护性和有害性表现。最近，沙利度胺（α-N-邻苯二甲酰亚胺戊二酰亚胺）在体内和体外均被证明可以部分抑制单核细胞 TNF α 的产生（50-70%）。然而，可能需要更有效地抑制 TNF α，以将宿主从 TNF α 介导的炎症的更严重和更广泛的毒性中拯救出来。 材料和方法：基于对 TNF α 产生的活性增加，选择沙利度胺的三种结构类似物进行研究。使用 ELISA 和 Northern blot 杂交，在人外周血单核细胞培养物中体外测试母体药物和类似物对脂多糖 (LPS) 诱导的细胞因子蛋白和 mRNA 产生的影响。然后，这些药物的体外作用在 LPS 诱导致死的小鼠模型中得到了体内证实。结果：与母体药物沙利度胺相比，新化合物（两种酯和一种酰胺）显示出对 LPS 刺激的人单核细胞产生 TNF α 的抑制作用增强。类似物和母体药物增强了白细胞介素 10 (IL-10) 的产生，但对 IL-6 和 IL-1 β 蛋白和 mRNA 的产生几乎没有影响。体内测试时，酰胺类似物可保护 80% 的 LPS 治疗小鼠免于因内毒素引起的休克而死亡。结论：旨在更好地抑制体外 TNF α 产生的沙利度胺类似物在体内具有相应更大的功效。这些发现可能对治疗以急性和大量 TNF α 产生为特征的人类疾病（例如结核性脑膜炎或中毒性休克）具有治疗意义。
Background: Tumor necrosis factor or (TNF alpha) is thought to mediate both protective and detrimental manifestations of the inflammatory response. Recently, thalidomide (alpha-N-phthalimidoglutarimide) was shown to partially inhibit monocyte TNF alpha production (by 50-70%) both in vivo and in vitro. More efficient inhibition of TNF alpha may, however, be necessary to rescue the host from more acute and extensive toxicities of TNF alpha-mediated inflammation.Materials and Methods: Three structural analogues of thalidomide were selected for study based on increased activity against TNF alpha production. The parent drug and the analogs were tested in vitro in human peripheral blood mononuclear cell cultures for their effects on lipopolysaccharide (LPS) induced cytokine protein and mRNA production using ELISAs and Northern blot hybridization. The in vitro effects of the drugs were then confirmed in vivo in a mouse model of LPS induced lethality.Results: The new compounds (two esters and one amide) showed increased inhibition of TNF alpha production by LPS-stimulated human monocytes, relative to the parent drug thalidomide. The analogs and the parent drug enhanced the production of interleukin 10 (IL-10), but had little effect on IL-6 and IL-1 beta protein and mRNA production. When tested in vivo, the amide analog protected 80% of LPS-treated mice against death from endotoxin induced shock.Conclusions: Analogs of thalidomide designed to better inhibit TNF alpha production in vitro have correspondingly greater efficacy in vivo. These finding may have therapeutic implication for the treatment of human diseases characterized by acute and extensive TNF alpha production such as tuberculous meningitis or toxic shock.